The rationale for this application is to take action to improve/expand HCV treatment options, an issue that effects ~10% of veterans. While chronic HCV infection can lead to liver steatosis, insulin resistance, chronic inflammation, and fibrosis, and hepatocellular carcinoma, the astronomical cost of the new HCV antivirals represents a significant burden on the VA healthcare system and the risk of viral escape has not been determined in less than ideal compliance populations. To address the need for more affordable HCV antivirals with high barriers to viral resistance and/or strategies to shorten the current treatment duration, our goal is to develop affordable therapeutic regimens to prevent HCV entry/spread and test the efficacy of those inhibitors for treating HCV infection. Viral entry into cells is often an effective antiviral drug target. In addition, blocking viral cell-to-cell spread has been suggested to enhance antiviral drug efficacy, limit viral escape, and enhance drug synergy. Relevant to Aim 1 of this proposal, studies in chronically HCV infected chimeric mice with humanized livers have shown that an entry/spread inhibitor alone can reduce and even clear HCV infection when administered as monotherapy. Relevant to Aim 2 of this proposal, we and others have shown that HCV entry inhibitors act synergistically with HCV direct acting antivirals (DAA) resulting in more rapid viral clearance, allowing for shorter treatment while also reducing viral escape Importantly, we recently discovered that the Niemann-Pick C1 Like-1 (NPC1L1) cellular cholesterol uptake receptor is required for HCV entry into hepatocytes and that ezetimibe, an FDA-approved drug that inhibits NPC1L1-mediated cholesterol uptake potently blocks HCV entry in human hepatoma cells and human hepatocytes transplanted into uPA-SCID mice.. Further, retrospective analysis of the National VA database using multivariable logistic regression models to control for age, sex, race, alcohol use, drug use, and other co-morbidities, we found HCV prevalence to be lower (p <.001) and IFN/RBV treatment response to be better (i.e. larger viral log reduction) in patients taking ezetimibe. Hence, the specific objective of this application is to assess the efficacy of EZE for the treatment of chronic HCV. Based on preliminary in vitro, in vivo, clinical retrospective data and HCV/DAA modeling, we hypothesize that when administered as monotherapy EZE will reduce HCV viremia perhaps allowing for viral clearance and that when included in combination treatment regimens that EZE will augment 2nd phase HCV decline resulting in faster viral clearance (i.e. shorter/cheaper DAA therapy). To test these hypotheses, we have assembled an interdisciplinary team of basic researchers, mathematical modelers, and clinicians to execute the following aims: (1) Assess the efficacy of EZE monotherapy in chronically HCV infected and predict time to cure; (2) Assess the efficacy of EZE as an adjunct therapy in chronically HCV infected patients undergoing currently approved HCV DAA treatment. Importantly, veterans are not only the ideal study population, but also would derive immediate benefit if the proposed study confirms that EZE improves HCV outcomes and/or can shorten DAA treatment. Additionally, this study would provide proof-of-concept regarding the importance of blocking viral cell-to-cell spread as part of an optimal antiviral strategy advancing knowledge about drug synergy and increasing the barrier to viral escape, a critical concern for all emerging RNA viruses the might affect our troops. Finally, our mathematical modeling focus ensures that the data generated will provide inherently useful HCV DAA kinetic information to help determine if modeling can be individualized in real time to inform about duration of therapy required to cure infection.